Streptococcus pneumoniae is the most common cause of community-acquired pneumonia accounting for 40,000 deaths/year in the US. Individuals who are most susceptible to pneumococcal pneumonia include those who are energy malnourished as a secondary consequence of chronic diseases such as cancer, emphysema, and AIDS. The mechanisms responsible for impaired innate immunity against bacterial infections arising from energy malnutrition are poorly understood. Leptin is hormone produced by adipose tissue that is reduced in the energy malnourished and is known to regulate innate immune responses. We have observed that leptin-deficient mice are more susceptible to bacterial pneumonia and alveolar macrophages (AMs) and neutrophils (PMNs) obtained from these animals exhibit defects in phagocytosis and killing of bacteria in vitro. The exogenous administration of leptin in vivo and in vitro to leptin-deficient animals reconstitutes antibacterial host defense endpoints in vivo and in vitro. We hypothesize that leptin regulates alveolar macrophage effector functions, neutrophil recruitment, and cytokine and leukotriene synthesis in the innate immune response against Streptococcus pneumoniae in vivo and in vitro. To test this hypothesis we will explore the following aims: 1) Assess the role of endogenous leptin in survival, bacterial clearance, and cellular recruitment following S. pneumoniae challenge by blocking leptin receptor signaling in vivo using a pharmacologic antagonist and leptin receptor transgenic mice; 2) Determine the kinetics and cellular sources of leptin production during the course of pneumococcal pneumonia and the target cells in the lung for its action; 3) Examine the importance of distinct leptin receptor signaling pathways in AM and PMN phagocytosis and killing of S. pneumoniae in vitro using cells from leptin receptor signaling mutant mice; and 4) Determine the effects of leptin administered at different time points following S. pneumoniae administration on bacterial clearance, survival, and AM and PMN mechanisms of phagocytosis and killing in normal mice. These studies will, for the first time, define leptin production and responses in the context of bacterial pneumonia and provide novel insights into the mechanisms by which leptin regulates innate immune responses against bacterial pathogens. They will also test the use of exogenous leptin as an adjunctive therapeutic agent in the treatment of pneumococcal pneumonia.